Drs Abul-Ainine and Steer have provided cogent arguments for the use of a 10mg/kg loading dose of intravenous aminophylline to treat acute asthma in children.[1] Their pharmacokinetic evidence for this dose is supported by Yung et al’s randomised placebo controlled trial using this same loading dose.[2] This study recruited 163 children with severe acute asthma unresponsive to three nebulised doses...
Drs Abul-Ainine and Steer have provided cogent arguments for the use of a 10mg/kg loading dose of intravenous aminophylline to treat acute asthma in children.[1] Their pharmacokinetic evidence for this dose is supported by Yung et al’s randomised placebo controlled trial using this same loading dose.[2] This study recruited 163 children with severe acute asthma unresponsive to three nebulised doses of 5mg Salbutamol in an intensive care setting. Those receiving aminophylline did not achieve a significant reduction in hospital stay, which was the primary outcome criteria, but in a sub set of 48 children who were able to perform lung function, there was a mean difference in FEV1% predicted of around 10% favouring aminophylline during the first 24 hours of the study. Oxygen saturations were also improved and, most importantly, 5 subjects in the placebo group were intubated and ventilated with none in the aminophylline group. These data suggest that there is a place for Aminophylline to treat the most severely affected children with acute asthma but its use has to be balanced against risks of toxicity and the high incidence of nausea and vomiting side effects. The latter occured in two thirds of the children in the Yung study and was of such severity that the aminophylline infusions were discontinued in one third of their patients. Such problems are reported less frequently after lower bolus doses.[3]
The use of aminophylline was discussed at length at the BTS – SIGN open meeting in Edingburgh in October 2001. Three important points were emphasized: (i) Frequent doses of nebulised ipratropium in addition to salbutamol, a treatment option not included in the Yung study, are a more preferable first line option with a low risk of side effects, (ii) Early bolus doses of 15mcg/kg of intravenous salbutamol are well tolerated and an effective adjunct in children poorly responsive to initial nebuliser treatment,[4] (iii) Current UK practice for aminophylline dosage as stated in the BNF is for a 5mg/kg bolus.
Unfortunately there is little evidence for the use of continuous intravenous salbutamol in addition to nebuliser treatment,[5] but it was the decision of the evidence review group to recommend bolus IV salbutamol and a subsequent infusion where indicated before the use of aminophylline. Such recommendations cannot be made unreservedly. Good comparative studies are still needed and in particular a randomised controlled trial comparing a bolus of IV salbutamol followed by maintenance infusion with bolus aminophylline and infusion in sufficient doses to achieve therapeutic levels early in the course of treatment. The BTS-SIGN guideline is subject to ongoing review and web based versions will be updated in the light of new evidence as it becomes available. The Yung study has now been included in the updated Cochrane Review of intravenous aminophylline and has upgraded the meta-analysis of evidence in favour of its use.[6] Given that this single study contributes 163 of the 380 children included and is the only study with measurable benefits, it is reasonable to consider revising the recommended aminophylline bolus dose to 10mg/kg given over 1 hour for use in the small number of children with life threatening bronchospasm unresponsive to maximal doses of other bronchodilators and steroids . However, there is insufficient evidence for the use of aminophylline to treat less severe cases and given present evidence no recommendations can be made about the dose of aminophylline if used in addition to intravenous salbutamol.
References
(1) Abul-Ainine A, Steer CR. Aminophylline and the British Asthma Guidelines In Children [electronic response to British Guideline on the Management of Asthma, Chapter 4]
thoraxjnl.com 2004http://thorax.bmjjournals.com/cgi/eletters/58/suppl_1/17i#193
(2) Yung M, South M. Randomised controlled trial of aminophylline for severe acute asthma. Arch Dis Child 1998;79:405-410(3)
(3) G Roberts1,2, D Newsom3, K Gomez2, A Raffles4, S Saglani4, J Begent4, P Lachman3, K Sloper5, R Buchdahl6 and A Habel2 On Behalf Of The North West Thames Asthma Study Group Intravenous salbutamol bolus compared with an aminophylline infusion in children with severe asthma: a randomised controlled trial Thorax 2003;58:306-310
(4) Browne GJ, Penna AS, Phung X, et al. Randomised trial of intravenous salbutamol in early management of acute asthma in children. Lancet 1997;349:301–5.
(5) Travers A, Jones AP, Kelly K, Barker SJ, Camargo CA Jr., Rowe BH Intravenous beta2-agonists for acute asthma in the emergency department (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software.
(6) Mitra A, Bassler D, Ducharme FM Intravenous aminophylline for acute severe asthma in children over 2 years using inhaled bronchodilators (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software.
I read with interest the recent publication by Subharta Moitra et al in Thorax.(1) The authors concluded that adult asthmatics have a higher risk of developing obesity than non-asthmatics. An association was found especially in non-atopic asthmatics with longer disease duration and the use of oral corticosteroids (OCS).
Obesity is the strongest risk factor for sleep apnea, and sleep apnea is associated also with asthma.(2) Obesity has been regarded also as a risk factor for developing asthma,(3) but the reverse association is still not clear. Both asthma and obesity begin often in early childhood, and they may share a common background.(3)
The relationships between smoking, physical activity, use of OCS and lung function were discussed in the paper. But why would asthma per se increase weight? Obesity may be considered also as a central nervous system disorder. Obesity and sleep apnea are associated with asthma. Short night sleep, sleep deprivation and chronic insomnia are associated with the development of obesity.(4) Studies have also shown an association between anxiety, depressive symptoms and the development of obesity.(4)
The ECHRS cohort was initiated in 1990. The study was focused on asthma, and unfortunately the original questionnaires did not include questions on sleep, sleep disorders or mental health. Also, no sleep studies or psychological testing were done. This explains the lack of information on anxiety, depres...
I read with interest the recent publication by Subharta Moitra et al in Thorax.(1) The authors concluded that adult asthmatics have a higher risk of developing obesity than non-asthmatics. An association was found especially in non-atopic asthmatics with longer disease duration and the use of oral corticosteroids (OCS).
Obesity is the strongest risk factor for sleep apnea, and sleep apnea is associated also with asthma.(2) Obesity has been regarded also as a risk factor for developing asthma,(3) but the reverse association is still not clear. Both asthma and obesity begin often in early childhood, and they may share a common background.(3)
The relationships between smoking, physical activity, use of OCS and lung function were discussed in the paper. But why would asthma per se increase weight? Obesity may be considered also as a central nervous system disorder. Obesity and sleep apnea are associated with asthma. Short night sleep, sleep deprivation and chronic insomnia are associated with the development of obesity.(4) Studies have also shown an association between anxiety, depressive symptoms and the development of obesity.(4)
The ECHRS cohort was initiated in 1990. The study was focused on asthma, and unfortunately the original questionnaires did not include questions on sleep, sleep disorders or mental health. Also, no sleep studies or psychological testing were done. This explains the lack of information on anxiety, depression, sleep duration, sleep deprivation, snoring and sleep apnea. As these factors are linked to both asthma and obesity, it is difficult to conclude that asthma would be directly related to the development of obesity. A minor problem in this prospective study is also that only 30% of the original members in the cohort (collected 1990-1994) were included in the ECHRS III. Altogether 10,681 subjects were lost to follow-up leaving 5,901 subjects in the third phase. Did those with missing information differ in characteristics from the remaining study subjects?
In sum, obesity is a huge problem, and asthma is an important disease. Understanding the associations between obesity and asthma is important. Could the association be explained by shared associations with sleep-disordered breathing and/or insomnia and/or sleep deprivation and/or anxiety and/or depression, or other common risk factors for both asthma and obesity?
REFERENCES
1. Moitra S, Carsin AE, Abramson MJ, Accordini S, Amaral AFS, Anto J, . . . Garcia-Aymerich J. Long-term effect of asthma on the development of obesity among adults: an international cohort study, ECRHS. Thorax 2022. 10.1136/thoraxjnl-2021-217867
2. Thompson C, Legault J, Moullec G, Baltzan M, Cross N, Dang-Vu TT, . . . Gosselin N. A portrait of obstructive sleep apnea risk factors in 27,210 middle-aged and older adults in the Canadian Longitudinal Study on Aging. Scientific Reports 2022;12. 10.1038/s41598-022-08164-6
3. Litonjua AA, Gold DR. Asthma and obesity: common early-life influences in the inception of disease. J Allergy Clin Immunol 2008;121:1075-84; quiz 85-6. 10.1016/j.jaci.2008.03.005
4. Sivertsen B, Lallukka T, Salo P, Pallesen S, Hysing M, Krokstad S, Simon O. Insomnia as a risk factor for ill health: results from the large population-based prospective HUNT Study in Norway. J Sleep Res 2014;23:124-32. 10.1111/jsr.12102
We have read with interest the letter from Dr. Eisenhut in this issue of the Journal and thank him for his comments on our work. The theory regarding reduced Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction in acute respiratory distress syndrome (ARDS) is interesting, though remains speculative at present. While some rationale exists to explain why transmembrane ion channels may be dysregulated in inflammation,1 we did not directly examine CFTR function in our original work.2 To test this hypothesis, direct augmentation of CFTR function during a nasal potential difference reading, or measurement of sweat chloride concentration, or another surrogate measure of CFTR function, would need to additionally be incorporated into our study design. We are not aware of any published studies of directly measured CFTR function in adults with ARDS.
References
1. Eisenhut M, Wallace H. Ion channels in inflammation. Pflugers Arch 2011; 461(4): 401-21.
2. MacSweeney R, Reddy K, Davies JC, et al. Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome. Thorax 2021; 76(11): 1099-107.
3. Davis PB, Del Rio S, Muntz JA, Dieckman L. Sweat chloride concentration in adults with pulmonary diseases. Am Rev Respir Dis 1983; 128(1): 34-7.
MacSweeney et al. in their recent report of transepithelial nasal potential difference measurements in patients at risk of acute respiratory distress syndrome documented that the amiloride response of nasal respiratory epithelium was significantly greater in patients who progressed to develop ARDS compared to those who did not (1). It was also greater in patients who died with ARDS compared to survivors. This is consistent with an increased epithelial sodium channel function in patients at risk of ARDS and its associated mortality. We previously conducted nasal potential difference measurements in children with and without meningococcal septicemia associated pulmonary edema and controls on a Pediatric Intensive Care Unit (2). We found that the amiloride response was greater in patients with pulmonary edema compared to controls but this effect did not reach statistical significance which may have been due to the small number of patients we could enrol (n=4 with pulmonary edema, n=2 with septicemia without pulmonary edema and 8 controls) (2). Despite this small number of patients we found that the nasal potential response to a low chloride solution in patients with septicemia associated pulmonary edema compared to controls was significantly reduced indicating a concomitant dysfunction of respiratory epithelial chloride channels.
It is known from in vitro studies that the epithelial sodium channel is inhibited by the Cystic Fibrosis Transmembrane Conductance Regulator (...
MacSweeney et al. in their recent report of transepithelial nasal potential difference measurements in patients at risk of acute respiratory distress syndrome documented that the amiloride response of nasal respiratory epithelium was significantly greater in patients who progressed to develop ARDS compared to those who did not (1). It was also greater in patients who died with ARDS compared to survivors. This is consistent with an increased epithelial sodium channel function in patients at risk of ARDS and its associated mortality. We previously conducted nasal potential difference measurements in children with and without meningococcal septicemia associated pulmonary edema and controls on a Pediatric Intensive Care Unit (2). We found that the amiloride response was greater in patients with pulmonary edema compared to controls but this effect did not reach statistical significance which may have been due to the small number of patients we could enrol (n=4 with pulmonary edema, n=2 with septicemia without pulmonary edema and 8 controls) (2). Despite this small number of patients we found that the nasal potential response to a low chloride solution in patients with septicemia associated pulmonary edema compared to controls was significantly reduced indicating a concomitant dysfunction of respiratory epithelial chloride channels.
It is known from in vitro studies that the epithelial sodium channel is inhibited by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel by reducing its average open probability and channel expression at the cell surface (3).
I therefore propose that the findings of MacSweeney et al. are due to a reduced CFTR function caused by the cytokine storm found in ARDS (4). We found unequivocal and reproducible evidence of a reduced CFTR function in patients with septicaemia induced pulmonary edema as reflected in significantly elevated sweat chloride levels in patient with pulmonary edema compared to controls with the same infection but no lung injury and compared to those without any infection (2). One patient we previously reported had a temporarily elevated sweat chloride level consistent with cystic fibrosis indicating as severe and transient impairment of systemic CFTR function (5). The reduced CFTR function results then in increased ENaC function found by the investigators and also found in patients with cystic fibrosis where this results from a wide range of causes of CFTR dysfunction (6).
References:
1. Mac Sweeney R, Reddy K, Davies JC, et al. Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome.Thorax 2021;76:1099-1107.
2. Eisenhut M, Wallace H, Barton P, Gaillard E, Newland P, Diver M, Southern KW.Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport.Pediatr Crit Care Med. 2006 Mar;7(2):119-24.
3. Rauh R, Hoerner C, Korbmacher C. δβγ-ENaC is inhibited by CFTR but stimulated by cAMP in Xenopus laevis oocytes. Am J Physiol Lung Cell Mol Physiol. 2017 Feb 1;312(2):L277-L287. doi: 10.1152/ajplung.00375.2016. Epub 2016 Dec 9. PMID: 27941075.
4. Eisenhut M Wallace H.Ion channels in inflammation.Pflugers Arch. 2011 Apr;461(4):401-21.
5. Eisenhut M, Southern KW.Positive sweat test following meningococcal septicaemia.Acta Paediatr. 2002;91(3):361-2.
6. Taylor CJ, Hardcastle J, Southern KW. Physiological measurements confirming the diagnosis of cystic fibrosis: the sweat test and measurements of transepithelial potential difference. Paediatr Respir Rev 2009 Dec;10(4):220-6.
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached...
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached and begins to decrease. For patients with DMD, this decline occurs around 13.5 (range-9-17) years of age.6 At this point, cough flows tend to drastically decrease, increasing the risk of pneumonia, but can be improved with air stacking.2,3 Therefore, it is our opinion that air stacking is not a burden but when to initiate is arguable.
References
1. Kang SW, Bach JR. Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease. Am J Phys Med Rehabil 2000;79(3):222-227.
2. Bach JR, Kang SW. Disorders of ventilation: weakness, stiffness, and mobilization. Chest 2000; 117(2):301-303.
3. Kang SW, Bach JR. Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease. Am J Phys Med Rehabil 2000;79(3):
4. Rideau Y, Bach J. Efficacité therapeutique dans la dystrophie musculaire de Duchenne. J Readapt Med 1982;2(3):96-100.
5. Deo P, Bach JR. Noninvasive ventilatory support to reverse weight loss in Duchenne muscular dystrophy: a case series. Pulmonol 2019;25(2):79-82.
6. Bach J, Alba A, Lee M, Rideau Y. Long-term respiratory rehabilitation in the treatment of neuromuscular disease. Ann Readapt Med Phys 1983;26:101-109.
We appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
We appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
Despite the clear benefits of LVR during exacerbations and in individuals with lower pulmonary function, the optimal timing for routine LVR therapy was not identified in our study of younger individuals with preserved lung function. While it would be ideal to conduct a randomized trial of LVR therapy in individuals with DMD beginning at the apex of their vital capacity trajectory,[9] a lengthy and costly study would be needed to evaluate changes over several years in order to determine the benefits of LVR. In contrast, such a study is not needed in individuals with advanced disease, in whom there is sufficient evidence to justify regular treatment. Given that uptake of routine LVR therapy for individuals with neuromuscular disease is not uniform, additional evidence is still needed to guide best practices for clinical care. Further exploration is required to ensure that LVR is introduced when it will be of benefit to individuals with neuromuscular disease.
References
1. Birnkrant DJ, Bushby KM, Amin RS, et al. The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatric Pulmonology 2010;45(8):739-48.
2. Amin RM, I; Zielinski,D; Adderley,R; Carnevale,F; Chiang,J; Cote,A; Daniels,C; Daigneault,P; Harrison.C; Katz,S; Keilty,K; Majaesic,C; Moraes.T.J; Price,A; Radhakrishnan,D; Rapoport,A; Spier,S; Thavagnanam,S; Witmans,M; Canadian Thoracic Society. Pediatric home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline executive summary. Canadian Journal of Respiratory, Critical Care and Sleep Medicine 2017;1(1):7-36.
3. Hull J, Aniapravan R, Chan E, et al. British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax 2012;67 Suppl 1:i1-40.
4. Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med 2004;170(4):456-65.
5. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol 2018;17(4):347-61. doi: 10.1016/s1474-4422(18)30025-5 [published Online First: 2018/02/06]
6. Birnkrant DJ. The American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation. Pediatrics 2009;123 Suppl 4:S242-S44.
7. McKim DA, Katz SL, Barrowman N, et al. Lung Volume Recruitment Slows Pulmonary Function Decline in Duchenne Muscular Dystrophy. Archives of Physical Medicine and Rehabilitation 2012;93(7):1117-22.
8. Katz SL, Barrowman N, Monsour A, et al. Long-Term Effects of Lung Volume Recruitment on Maximal Inspiratory Capacity and Vital Capacity in Duchenne Muscular Dystrophy. Ann Am Thorac Soc 2016;13(2):217-22.
9. Chiou M, Bach JR, Jethani L, et al. Active lung volume recruitment to preserve vital capacity in Duchenne muscular dystrophy. J Rehabil Med 2017;49(1):49-53. doi: 10.2340/16501977-2144 [published Online First: 2016/09/16]
10. McDonald CM, Gordish-Dressman H, Henricson EK, et al. Longitudinal pulmonary function testing outcome measures in Duchenne muscular dystrophy: Long-term natural history with and without glucocorticoids. Neuromuscul Disord 2018;28(11):897-909. doi: 10.1016/j.nmd.2018.07.004 [published Online First: 2018/10/20]
Thank you to the authors for this important and detailed analysis. I write to simply draw attention to a discrepancy, unless I am mistaken, between the ATE frequency rates stated in the abstract and those in the main text.
Abstract: "The frequency rates of overall ATE, acute coronary syndrome, stroke and other ATE were 3.9% (95% CI 2.0% to to 3.0%, I2=96%; 16 studies; 7939 patients), 1.6% (95% CI 1.0% to 2.2%, I2=93%; 27 studies; 40 597 patients) and 0.9% (95% CI 0.5% to 1.5%, I2=84%; 17 studies; 20 139 patients), respectively".
Main text: "The weighted frequency of ATE was 4.0% (95%CI 2.0% to 6.5%, I2 =95%; 19 studies; 8249 patients), including myocardial
infarction/acute coronary syndrome (1.1%, 95%CI 0.2% to 3.0%, I2=96%; 16 studies; 7939 patients), ischaemic stroke (1.6%, 95%CI 1.0% to 2.2%, I2 =93%; 27 studies; 40597 patients) and other ATE (0.9%, 95%CI 0.5% to 1.5%; I2
=84%; 17 studies; 20139 patients)
The benefits of pulmonary rehabilitation for individuals with chronic respiratory diseases are well-documented1, but referral practices and programme completion have remained challenging. This has been exacerbated by the COVID-19 pandemic and shielding practices. Thus, highlighting the usefulness of developing a robust telerehabilitation programme as a substitute for centre-based programmes. The data gained from Cox et al addresses this area and demonstrates clinically meaningful advantages of telerehabilitation and is warmly welcomed. A detailed breakdown of the costs involved between both arms would be very helpful in assessing an overall equivalence of the two arms.
The CRQ is a validated tool for use in research; however, the use of its dyspnoea domain specifically has been shown to be less reliable in comparative research2. Other tools which may be a useful substitute for this study would be ‘incremental shuttle walking test’3 and ‘St George’s respiratory questionnaire’4.
The number of participants presenting to community healthcare services, and/or those requiring rescue therapy for a mild exacerbation (e.g., antibiotics and/or a short course of corticosteroids) not requiring presentation to a hospital, during the study and follow-up period, may be useful for further assessment of the equivalence of telerehabilitation versus centre-based programmes.
This study provides useful data regarding the potential benefits of incorporating telerehabilita...
The benefits of pulmonary rehabilitation for individuals with chronic respiratory diseases are well-documented1, but referral practices and programme completion have remained challenging. This has been exacerbated by the COVID-19 pandemic and shielding practices. Thus, highlighting the usefulness of developing a robust telerehabilitation programme as a substitute for centre-based programmes. The data gained from Cox et al addresses this area and demonstrates clinically meaningful advantages of telerehabilitation and is warmly welcomed. A detailed breakdown of the costs involved between both arms would be very helpful in assessing an overall equivalence of the two arms.
The CRQ is a validated tool for use in research; however, the use of its dyspnoea domain specifically has been shown to be less reliable in comparative research2. Other tools which may be a useful substitute for this study would be ‘incremental shuttle walking test’3 and ‘St George’s respiratory questionnaire’4.
The number of participants presenting to community healthcare services, and/or those requiring rescue therapy for a mild exacerbation (e.g., antibiotics and/or a short course of corticosteroids) not requiring presentation to a hospital, during the study and follow-up period, may be useful for further assessment of the equivalence of telerehabilitation versus centre-based programmes.
This study provides useful data regarding the potential benefits of incorporating telerehabilitation programmes as a part of health services. Further information regarding costs, presentations to community services, and justification of the use of the CRQ-D tool would be valuable.
REFERENCES:
1. Bolton CE, Bevan-Smith EF, Blakey JD, et alBritish Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICEThorax 2013;68:ii1-ii30.
2. Wijkstra PJ, TenVergert EM, Van Altena R, Otten V, Postma DS, Kraan J, Koëter GH. Reliability and validity of the chronic respiratory questionnaire (CRQ). Thorax. 1994 May;49(5):465-7. doi: 10.1136/thx.49.5.465. PMID: 8016767; PMCID: PMC474867.
3. Singh SJ, Jones PW, Evans R, Morgan MD. Minimum clinically important improvement for the incremental shuttle walking test. Thorax. 2008 Sep;63(9):775-7. doi: 10.1136/thx.2007.081208. Epub 2008 Apr 4. PMID: 18390634.
4. Paul W Jones (2005) St. George's Respiratory Questionnaire: MCID, COPD: Journal of Chronic Obstructive Pulmonary Disease, 2:1, 75-79, DOI: 10.1081/COPD-200050513
The state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).
The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).
Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
Observations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of...
The state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).
The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).
Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
Observations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of exuded plasma (14). Intriguingly, as demonstrated with Coronavirus229E and rhinoviruses (3,4,6,13), the plasma exudation response lasts until resolution.
Epithelial barrier asymmetry: exuded plasma operates on an intact airway mucosa.
Subepithelial extravasation of plasma is controlled by active, fully reversible formation of gaps between postcapillary, venular endothelial cells. The subsequent epithelial transmission of plasma reflects a direction-specific elasticity of cell junctions in pseudostratified epithelium. Thus, when approached from beneath by minimally increased basolateral hydrostatic pressure, plasma macromolecules pass outwardly by epithelial mechanisms not available to molecules deposited on the mucosal surface (2). Most important, plasma exudation proceeds without affecting the normal barrier function of the epithelial lining. In accord, inflammatory airways diseases exhibit plasma exudation without sign of increased penetration of molecules deposited on the airway mucosal surface (9,13,14). The conspicuous asymmetry of the pseudostratified epithelium of human airways makes the plasma exudation response, with its omnipotent content, a first line innate respiratory defense response (15).
Plasma exudation building barrier and biological milieu at sites of epithelial regeneration.
To the extent that Covid-19 causes airways epithelial injury and shedding (1), plasma exudation would again be vitally involved (13,15-17). As in asthma, infection-induced loss of pseudostratified epithelium apparently emerges as a patchy, non-sanguineous event without damage to the basement membrane. In experimental in vivo studies, such asthma-like denudation, almost independent of cause, promptly induces local plasma exudation that covers the naked membrane with a fibrin/fibronectin gel. Further, this provisional barrier-gel is continuously supplied by exuded plasma proteins creating a biological milieu suited for prompt start and speedy progress of repair. In vivo, all types of epithelial cells bordering a denuded patch dedifferentiate into fast-migrating regeneration cells. As soon as a cellular barrier is established exudation stops and the gel is shed (15-17). At vulnerable airway denudation patches, local plasma exudation would contribute both a barrier and a biologically active milieu promoting antimicrobial defense and epithelial regeneration.
Summarizing: The above humoral aspect of mucosal defense in human airways with intact or regenerating epithelial lining is overlooked in currently leading notions (1). As listed elsewhere (2), numerous factors may contribute to this oversight. A major factor is unappreciation of the asymmetry of human airways epithelial barriers (15). Another concerns specificity. However, precision of airways plasma exudation resides not in molecular specificity but in its highly localized distribution along with strict control of its duration (2). A further shortcoming of the present complementary concepts concerns the fact that they are underpinned by classical observational medical research, which was outdated already in 1990s (18). Word count 595
References
1. Bridges JP, Vladar EK, Huang H, Mason RJ. Respiratory epithelial cell responses to SARS-CoV-2 in COVID-19. Thorax 2022;77:203-209.
2. Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health. Am J Physiol Lung Cell Mol Physiol 2022;322:L503-L506. Doi:10.1152ajplung.00470.2021.
3. Proud D, Naclerio RM, Gwaltney JM, Hendley JO. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis. 1990;161:120-123.
4. Åkerlund A, Greiff L, Andersson M, Bende M, Alkner U, Persson C. Mucosal exudation of fibrinogen in coronavirus-induced common colds. Acta Otolaryngol. 1993;113:642-648.
5. Pizzichini MMM, Pizzicini E, Efthimiadis A, et al. Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study. Am J Respir Crit Care Med. 1998;158:1178-1184.
6. Winther B, Gwaltney JM Jr, Humphries JE, Hendley JO. Cross- linked fibrin in the nasal fluid of patients with common cold. Clin Infect Dis. 2002;34:708-710.
7. Stockley RA, Mistry M, Bradwell AR, Burnett D. A study of plasma proteins in the sol phase of sputum from patients with chronic bronchitis. Thorax. 1979;34:777-782
8. Van Vyve T, Chanez P, Bernard A, et al. Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects. J Allergy Clin Immunol. 1995;95:60-68.
9. Greiff L, Andersson M, Åkerlund A, et al. Microvascular exudative hyperresponsiveness in human coronavirus-induced common cold. Thorax. 1994;49:121-127.
10. Greiff L, Andersson M, Erjefalt JS, Svensson C, Persson CG. Loss of size- selectivity at histamine-induced exudation of plasma proteins in atopic nasal airways. Clin Physiol Funct Imaging. 2002;22:28-31.
11. Andersson M, Michel L, Llull JB, Pipkorn U. Complement activation on the nasal mucosal surface – a feature of the immediate allergic reaction in the nose. Allergy. 1994;49:242-245.
12. Svensson C, Baumgarten CR, Pipkorn U, Alkner U, Persson C. Reversibility and reproducibility of histamine-induced plasma leakage in nasal airways. Thorax. 1989;44:13-18.
13. Persson C. Humoral first-line mucosal innate defence in vivo. J Innate Immun. 2020;2020(12):373-386.
14. Liu MC, Xiao HQ, Brown AJ, Ritter CS, Schroeder J. Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung. Clin Exp Allergy. 2012;42:383-391.
15. Persson C. ‘Bedside’ observations challenge aspects of the ‘Epithelial barrier hypothesis’. Nat Rev Immunol 2021;21:829. https://doi.org/ 10.1038/s41577-021- 00650-8.
16. Persson CGA, Erjefält JS. Airway epithelial restitution following shedding and denudation. In: Crystal RG, West JB, Weibel ER, Barnes PJ, eds. The Lung: Scientific Foundations, 2nd edn. New York: Raven; 1997:2611-2627.
17. Persson C. Airways exudation of plasma macromolecules: innate defense, epithelial regeneration, and asthma. J Allergy Clin Immunol. 2019;143:1271–1286.
18. Persson C. Clinical research, or classical clinical research? Nat Med. 1999;5(7):714-715.
We recently read the recent publication by Elköf and colleagues in the recent issue of Thorax titled ‘Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease’(1) with great interest. The paper highlights an important clinical observation in a well-defined cohort.
We were interested that Elköf and colleagues, tentatively discuss that biological mechanisms resulting from ICS alterations on the immune system may be an explanation for a change in the microbial composition in the airways(1). As the authors discussed, eosinophilic inflammation in COPD identifies a group of patients with ICS responsiveness(2). In the mouse model, there are data examining that eosinophils have anti-microbial properties(3). Access to eosinophil counts from this cohort may be invaluable in unravelling the relationship of eosinophils and COPD and could provide insight into the impact of steroids in bacterial infection. Did the authors investigate the peripheral blood eosinophil count as a covariate in their main analyses?
References
1. Eklöf J, Ingebrigtsen TS, Sørensen R, Saeed MI, Alispahic IA, Sivapalan P, et al. Use of inhaled corticosteroids and risk of acquiring <em>Pseudomonas aeruginosa</em> in patients with chronic obstructive pulmonary disease. Thorax. 2021:thoraxjnl-2021-217160.
2. Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al....
We recently read the recent publication by Elköf and colleagues in the recent issue of Thorax titled ‘Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease’(1) with great interest. The paper highlights an important clinical observation in a well-defined cohort.
We were interested that Elköf and colleagues, tentatively discuss that biological mechanisms resulting from ICS alterations on the immune system may be an explanation for a change in the microbial composition in the airways(1). As the authors discussed, eosinophilic inflammation in COPD identifies a group of patients with ICS responsiveness(2). In the mouse model, there are data examining that eosinophils have anti-microbial properties(3). Access to eosinophil counts from this cohort may be invaluable in unravelling the relationship of eosinophils and COPD and could provide insight into the impact of steroids in bacterial infection. Did the authors investigate the peripheral blood eosinophil count as a covariate in their main analyses?
References
1. Eklöf J, Ingebrigtsen TS, Sørensen R, Saeed MI, Alispahic IA, Sivapalan P, et al. Use of inhaled corticosteroids and risk of acquiring <em>Pseudomonas aeruginosa</em> in patients with chronic obstructive pulmonary disease. Thorax. 2021:thoraxjnl-2021-217160.
2. Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. 2018;6(2):117-26.
3. Linch SN, Kelly AM, Danielson ET, Pero R, Lee JJ, Gold JA. Mouse eosinophils possess potent antibacterial properties in vivo. Infection and immunity. 2009;77(11):4976-82.
Dear Editor
Drs Abul-Ainine and Steer have provided cogent arguments for the use of a 10mg/kg loading dose of intravenous aminophylline to treat acute asthma in children.[1] Their pharmacokinetic evidence for this dose is supported by Yung et al’s randomised placebo controlled trial using this same loading dose.[2] This study recruited 163 children with severe acute asthma unresponsive to three nebulised doses...
Dear Editor,
I read with interest the recent publication by Subharta Moitra et al in Thorax.(1) The authors concluded that adult asthmatics have a higher risk of developing obesity than non-asthmatics. An association was found especially in non-atopic asthmatics with longer disease duration and the use of oral corticosteroids (OCS).
Obesity is the strongest risk factor for sleep apnea, and sleep apnea is associated also with asthma.(2) Obesity has been regarded also as a risk factor for developing asthma,(3) but the reverse association is still not clear. Both asthma and obesity begin often in early childhood, and they may share a common background.(3)
The relationships between smoking, physical activity, use of OCS and lung function were discussed in the paper. But why would asthma per se increase weight? Obesity may be considered also as a central nervous system disorder. Obesity and sleep apnea are associated with asthma. Short night sleep, sleep deprivation and chronic insomnia are associated with the development of obesity.(4) Studies have also shown an association between anxiety, depressive symptoms and the development of obesity.(4)
The ECHRS cohort was initiated in 1990. The study was focused on asthma, and unfortunately the original questionnaires did not include questions on sleep, sleep disorders or mental health. Also, no sleep studies or psychological testing were done. This explains the lack of information on anxiety, depres...
Show MoreWe have read with interest the letter from Dr. Eisenhut in this issue of the Journal and thank him for his comments on our work. The theory regarding reduced Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction in acute respiratory distress syndrome (ARDS) is interesting, though remains speculative at present. While some rationale exists to explain why transmembrane ion channels may be dysregulated in inflammation,1 we did not directly examine CFTR function in our original work.2 To test this hypothesis, direct augmentation of CFTR function during a nasal potential difference reading, or measurement of sweat chloride concentration, or another surrogate measure of CFTR function, would need to additionally be incorporated into our study design. We are not aware of any published studies of directly measured CFTR function in adults with ARDS.
References
1. Eisenhut M, Wallace H. Ion channels in inflammation. Pflugers Arch 2011; 461(4): 401-21.
2. MacSweeney R, Reddy K, Davies JC, et al. Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome. Thorax 2021; 76(11): 1099-107.
3. Davis PB, Del Rio S, Muntz JA, Dieckman L. Sweat chloride concentration in adults with pulmonary diseases. Am Rev Respir Dis 1983; 128(1): 34-7.
MacSweeney et al. in their recent report of transepithelial nasal potential difference measurements in patients at risk of acute respiratory distress syndrome documented that the amiloride response of nasal respiratory epithelium was significantly greater in patients who progressed to develop ARDS compared to those who did not (1). It was also greater in patients who died with ARDS compared to survivors. This is consistent with an increased epithelial sodium channel function in patients at risk of ARDS and its associated mortality. We previously conducted nasal potential difference measurements in children with and without meningococcal septicemia associated pulmonary edema and controls on a Pediatric Intensive Care Unit (2). We found that the amiloride response was greater in patients with pulmonary edema compared to controls but this effect did not reach statistical significance which may have been due to the small number of patients we could enrol (n=4 with pulmonary edema, n=2 with septicemia without pulmonary edema and 8 controls) (2). Despite this small number of patients we found that the nasal potential response to a low chloride solution in patients with septicemia associated pulmonary edema compared to controls was significantly reduced indicating a concomitant dysfunction of respiratory epithelial chloride channels.
Show MoreIt is known from in vitro studies that the epithelial sodium channel is inhibited by the Cystic Fibrosis Transmembrane Conductance Regulator (...
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached...
Show MoreWe appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
Despite the clear benefits of L...
Show MoreThank you to the authors for this important and detailed analysis. I write to simply draw attention to a discrepancy, unless I am mistaken, between the ATE frequency rates stated in the abstract and those in the main text.
Abstract: "The frequency rates of overall ATE, acute coronary syndrome, stroke and other ATE were 3.9% (95% CI 2.0% to to 3.0%, I2=96%; 16 studies; 7939 patients), 1.6% (95% CI 1.0% to 2.2%, I2=93%; 27 studies; 40 597 patients) and 0.9% (95% CI 0.5% to 1.5%, I2=84%; 17 studies; 20 139 patients), respectively".
Main text: "The weighted frequency of ATE was 4.0% (95%CI 2.0% to 6.5%, I2 =95%; 19 studies; 8249 patients), including myocardial
infarction/acute coronary syndrome (1.1%, 95%CI 0.2% to 3.0%, I2=96%; 16 studies; 7939 patients), ischaemic stroke (1.6%, 95%CI 1.0% to 2.2%, I2 =93%; 27 studies; 40597 patients) and other ATE (0.9%, 95%CI 0.5% to 1.5%; I2
=84%; 17 studies; 20139 patients)
The benefits of pulmonary rehabilitation for individuals with chronic respiratory diseases are well-documented1, but referral practices and programme completion have remained challenging. This has been exacerbated by the COVID-19 pandemic and shielding practices. Thus, highlighting the usefulness of developing a robust telerehabilitation programme as a substitute for centre-based programmes. The data gained from Cox et al addresses this area and demonstrates clinically meaningful advantages of telerehabilitation and is warmly welcomed. A detailed breakdown of the costs involved between both arms would be very helpful in assessing an overall equivalence of the two arms.
The CRQ is a validated tool for use in research; however, the use of its dyspnoea domain specifically has been shown to be less reliable in comparative research2. Other tools which may be a useful substitute for this study would be ‘incremental shuttle walking test’3 and ‘St George’s respiratory questionnaire’4.
The number of participants presenting to community healthcare services, and/or those requiring rescue therapy for a mild exacerbation (e.g., antibiotics and/or a short course of corticosteroids) not requiring presentation to a hospital, during the study and follow-up period, may be useful for further assessment of the equivalence of telerehabilitation versus centre-based programmes.
This study provides useful data regarding the potential benefits of incorporating telerehabilita...
Show MoreThe state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).
The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).
Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
Show MoreObservations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of...
We recently read the recent publication by Elköf and colleagues in the recent issue of Thorax titled ‘Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease’(1) with great interest. The paper highlights an important clinical observation in a well-defined cohort.
We were interested that Elköf and colleagues, tentatively discuss that biological mechanisms resulting from ICS alterations on the immune system may be an explanation for a change in the microbial composition in the airways(1). As the authors discussed, eosinophilic inflammation in COPD identifies a group of patients with ICS responsiveness(2). In the mouse model, there are data examining that eosinophils have anti-microbial properties(3). Access to eosinophil counts from this cohort may be invaluable in unravelling the relationship of eosinophils and COPD and could provide insight into the impact of steroids in bacterial infection. Did the authors investigate the peripheral blood eosinophil count as a covariate in their main analyses?
References
1. Eklöf J, Ingebrigtsen TS, Sørensen R, Saeed MI, Alispahic IA, Sivapalan P, et al. Use of inhaled corticosteroids and risk of acquiring <em>Pseudomonas aeruginosa</em> in patients with chronic obstructive pulmonary disease. Thorax. 2021:thoraxjnl-2021-217160.
Show More2. Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al....
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